This invention relates to methods and apparatus for transdermal medicament delivery and to improvements therein. More specifically, this invention relates to improved methods and apparatus for active (as opposed to passive) transdermal, ambulatory drug delivery. Yet more particularly, this invention relates to increasing the efficiency of iontophoresis devices and to improved methods of making and using such devices.
Iontophoresis, according to Dorland's Illustrated Medical Dictionary, is defined to be "the introduction, by means of electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes." Iontophoretic devices have been known since the early 1900's. British patent specification 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices known to the art at that time, namely the requirement of a special low tension (low voltage) source of current which meant that the patient needed to be immobilized near such source. The device of that British specification was made by forming from the electrodes and the material containing the medicament or drug to be delivered transdermally, a galvanic cell which itself produced the current necessary for iontphoretically delivering the medicament. This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily occupation.
Recently, there has been considerable interest in iontophoresis. Iontophoresis has been found to be useful in the transdermal administration or introduction of lidocaine hydrochloride, hydrocortisone, acetic acid, flouride, penicillin, dexamethasone sodium phosphate, and many other drugs. Perhaps the widest use of iontophoresis is to induce sweating by the iontophoretic delivery of pilocarpine nitrate into the skin. The sweat so produced is analyzed in a screening procedure for the detection of cystic fibrosis.
In presently known iontophoresis devices, at least two electrodes are used. Both these electrodes are disposed so as to be in intimate electrical contact or electrical communication with some portion of the skin. The "active" electrode is the electrode from which the ionic drug is delivered into the body. The "indifferent" ground or counter electrode serves to close the electrical circuit through the body. A battery or other current source is coupled to the electrode to provide the electromotive force (i.e., repulsion) to drive the drug into the body. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, then the negative electrode will be the active electrode and the positive electrode will be the indifferent electrode. Of course, simultaneous delivery of drugs from both of the electrodes is also possible.
Generally, iontophoresis electrodes include a reservoir of the drug, typically incorporated in the form of a salt of the drug, for example a fluoride or sulfate. These reservoirs may take the form of preformed gel bodies, such as disclosed in U.S. Pat. No. 4,382,529 issued to Webster, solid adhesive bodies as disclosed in U.S. Pat. No. 4,416,274, issued to Jacobson, or fluid reservoirs as disclosed in U.S. Pat. No. 4,250,878, issued to Jacobsen. Electrical current is typically applied to the fluid reservoir by means of a current distributing member, which may take the form of a metal plate, a foil layer, a conductive screen, or a dispersion of conductive particles within the drug reservoir.
Typically, the current distributing member in iontophoresis electrodes has been constructed of an inert material, such as stainless steel or platinum. However, more recently use of sacrificial current distributing members which are themselves oxidized or reduced during delivery of the drug has been discussed. Use of sacrificial current distributing members can avoid the pH changes and other adverse effects associated with the hydrolysis of water which generally accompanies the use of inert current distributing members. Electrodes with sacrificial current distributing members are disclosed in U.S. Pat. No. 4,744,787, issued to Phipps et al, incorporated herein by reference in its entirety. Such electrodes are also discussed in the above-cited copending application by Untereker et al, also incorporated herein by reference in its entirety.
In this patent and copending application, the drug reservoir contains a counter ion which reacts with the electrochemically-generated ion from the sacrificial current distributing member to form a neutral or substantially insoluble compound. Preferably, the counter ion in the drug reservoir is provided by the drug salt. However, many drug salts do not possess the proper counter ion to effectively react with the electrochemically-generated ion. For example, use of a drug salt having only a nitrate counter ion would be difficult to use with a silver anode since the compound formed in the drug reservoir, silver nitrate, is water soluble. The addition of a nondrug salt (e.g., NaCl) can be made to the drug reservoir to provide the proper counter ion (e.g., Cl.sup.-) for use with, a particular sacrificial electrode (e.g., Ag). This approach produces extraneous nondrug coions (e.g., Na.sup.+) which can effectively compete with drug ion delivery to the skin. Thus, the efficiency of the iontophoresis device may be reduced.
An alternative approach to avoiding the adverse effects associated with hydrolysis of water at the current distributing member is disclosed in the published PCT patent application Ser. No. WO 87/04936, published Aug. 27, 1987, by Sanderson et al, corresponding to U.S. Pat. No. 4,722,726. This electrode system is also described in the article "Noninvasive Delivery of a Novel Ionotropic Catecholamine: Iontophoretic Versus Intravenous Infusion in Dogs" by Sanderson et al, published in the Journal of Pharmaceutical Sciences, Vol. 76, No. 3, March 1987, pp. 215-218. In this electrode system, an inert current distributing member is used and the electrode is divided into an upper chamber filled with a buffer and a lower chamber containing the ionic drug. The upper chamber is spacially separated from the lower chamber by an ion mobility inhibiting means such as an ion exchange membrane. As described, it is apparent that Sanderson et al intend that a buffer solution in the upper chamber be used to mitigate the effects of hydrolysis of water, and that the ion selective membrane isolate the drug from the contents of the upper chamber. The lower chamber of Sanderson et al includes a microporous membrane which permits electrical migration of ions (from the chamber to the skin) but which inhibits leakage of fluid from the device.
There are two disadvantages of the Sanderson et al device. First, use of this invention is practically restricted to devices using electrodes which generate H.sup.+ or OH.sup.- ions since buffering agents generally do not form neutral, insoluble products with other ions, e.g., Ag.sup.+ or Sn.sup.++ as would be electrochemically-generated ions from silver or tin electrodes respectively. Second, the solution or gel used to contain the buffering agents in Sanderson et al are susceptible to dry-out or other changes in physical properties during storage and use.
In electrodes including fluid reservoirs, as disclosed in U.S. Pat. No. 4,250,878 issued to Jacobson, delivery of the drug typically takes place through a microporous membrane. Typically, such membranes are permeable based on size, and therefore must be permeable to any ion equal to or smaller than the drug ion intended to be delivered. In U.S. Pat. No. 4,640,689, issued on Feb. 3, 1987 to Sibalis, an iontophoresis electrode including a gel type drug reservoir provided with a semipermeable membrane is disclosed. This reference also suggests the use of an "ion selective retention gel" intermediate the drug reservoir and the semipermeable membrane. The ion to be retained by the gel is not discussed.
Commonly owned pending application, Ser. No. 264,239, supra, discloses the use of a layer of charge selective material applied to the surface of the current distributing member to prevent electrochemically generated ions from migrating into the drug reservoir. The counter ion of the ionomer of the coating, e.g., Cl.sup.-, can be used to react with the electrochemically generated ion from the current distributing member, e.g., Ag.sup.+, to form an insoluble product, e.g., AgCl. In addition, the drug counter ion, e.g., Cl.sup.-, can migrate through the coating and react with the electrochemically generated species, e.g., Ag.sup.+. However, in some applications, the type or quantity of ion available from the charge selective membrane and the drug reservoir may not be sufficient to prevent the migration of electrochemically generated ions, particularly at high currents or long durations of use.